Methods of delivery of cetyl myristoleate

ABSTRACT

The invention provides novel and advantageous delivery devices for compositions of cetyl myristoleate. The delivery devices include transdermal delivery devices, suppositories, enteric coatings, and microencapsulation. Further provided are methods of treating diseases using the disclosed delivery devices. Diseases that can be treated with the devices include, but are not limited to, diseases associated with the inflammation of tissues, diseases associated with inflammatory conditions affecting joints, and autoimmune diseases.

BACKGROUND OF THE INVENTION

[0001] The invention relates to novel and advantageous methods ofdelivery of cetyl myristoleate. The delivery methods are useful in thetreatment of several diseases affecting humans and animals.

[0002] Cetyl myristoleate (CM) is found in and isolated from mice, inparticular, Swiss albino mice, sperm whales, and the anal glands of somespecies of male beavers. The compound can also be synthesized in thelaboratory using cetyl alcohol and myristoleic acid. The methods ofobtaining CM are described in U.S. Pat. Nos. 4,049,824, 4,113,881, and5,569,676. These patents are incorporated herein in their entirety.

[0003] CM can be used to treat diseases in humans and animals. CM isuseful in the treatment of diseases associated with the inflammation oftissues such as tendinitis, tenosynovitis, bursitis, chronic patellartendinitis, Achilles tendinitis, fibrositis, inflammation of the spine,colitis, bronchitis, polymyalagia rheumatica, Crohn's disease, primarybiliary cirrhosis, pericarditis, ulcerative colitis, and Sjogren'ssyndrome.

[0004] CM is also useful in the treatment of inflammatory conditionsthat affect joints such as arthritis, juvenile chronic arthritis,chronic arthritis, Behcet's disease, ankylosing spondylitis, mixedconnective tissue disease, Reiter's syndrome, and synovitis. Diehl andMay, (1994) J Pharm Sci 83(3):296-299.

[0005] Autoimmune diseases such as autoimmune Addison's disease,autoimmune hepatitis, Behcet's disease, lupus, antiphospholipidsyndrome, multiple sclerosis, and essential mixed cryoglobulinemia canbe treated with CM.

[0006] CM can also be used in the treatment of migraine, emphysema,asthma, myofascial pain, arteriosclerosis, joint sports injuries andsprains, insulin dependant diabetes, peripheral vascular disease, carpaltunnel syndrome, cardiomyopathy, chronic fatigue immune dysfunctionsyndrome, Churg-Strauss syndrome, and psoriasis.

[0007] CM can be delivered orally; however, absorption of waxy esterssuch as CM is low compared to other lipids and is therefore very poor.The administration of lipase digestive enzyme is presently recommendedalong with oral doses of CM to increase absorption. New methods ofdelivery are needed for CM that allow for the efficient absorption ofCM.

SUMMARY OF THE INVENTION

[0008] It is an object of the invention to provide transdermal deliverydevices, suppositories, enterically coated compositions, andmicroencapsulated compositions comprising cetyl myristoleate.

[0009] It is another object of the invention to provide methods oftreatment of various diseases affecting humans and animals by providingcetyl myristoleate compositions a human or animal in need thereof.

[0010] These and other objects of the invention are provided by one ormore of the embodiments described below.

[0011] One embodiment of the invention provides a transdermal deliverydevice for the delivery of cetyl myristoleate. The transdermal deliverydevice contains between 1 mg and 3000 mg of cetyl myristoleate.

[0012] Another embodiment of the invention provides for a transdermaldelivery device comprising a backing layer and a matrix layer underlyingthe backing layer. The matrix layer of the transdermal delivery devicecomprises a mixture of cetyl myristoleate and a pressure sensitiveadhesive.

[0013] Even another embodiment of the invention provides a transdermaldelivery device wherein the matrix layer further comprises one or moreof the components selected from the group consisting of glucosaminesulfate, chondroitin sulfate, sea cucumber extract, hydrolyzed sharkcartilage, collagen II, and methylsulfonylmethane.

[0014] Still another embodiment of the invention provides a transdermaldelivery device wherein the device is worn for between 5 and 10 days.

[0015] Yet another embodiment of the invention provides a transdermaldelivery device wherein between 0.01 mg/kg/day and 10 mg/kg/day of cetylmyristoleate is delivered.

[0016] A further embodiment of the invention provides a method oftreating a disease associated with the inflammation of tissues. Atransdermal delivery device comprising cetyl myristoleate is affixed tothe skin of an animal or human. The transdermal delivery device isuseful in treating diseases selected from the group consisting oftendinitis, tenosynovitis, bursitis, chronic patellar tendinitis,Achilles tendinitis, fibrositis, inflammation of the spine, colitis,bronchitis, polymyalagia rheumatica, Crohn's disease, primary biliarycirrhosis, pericarditis, ulcerative colitis, and Sjogren's syndrome.

[0017] Another embodiment of the invention provides a method of treatinga disease associated with an inflammatory condition that affects joints.A transdermal device comprising cetyl myristoleate is affixed to theskin of an animal or human. The disease to be treated is selected fromthe group consisting of arthritis, chronic arthritis, Behcet's disease,ankylosing spondylitis, mixed connective tissue disease, Reiter'ssyndrome and synovitis.

[0018] Even another embodiment of the invention provides a method oftreating an autoimmune disease. A transdermal device comprising cetylmyristoleate is affixed to the skin of an animal or human. The diseaseto be treated is selected from the group consisting of autoimmuneAddison's disease, autoimmune hepatitis, Behcet's disease, lupus,antiphospholipid syndrome, multiple sclerosis, and essential mixedcryoglobulinemia.

[0019] Still another embodiment of the invention provides an oralmedicament comprising cetyl myristoleate and an enteric coating. Theenteric coating is resistant to dissolution in the stomach butpredisposed to dissolution in the intestine so as to prevent release ofthe cetyl myristoleate until the medicament is in the intestine.

[0020] Yet another embodiment of the invention provides for an oralmedicament comprising cetyl myristoleate and an enteric coating. Theenteric coating is resistant to dissolution in an environment having apH less than 5.5.

[0021] A further embodiment of the invention provides for an oralmedicament comprising cetyl myristoleate and an enteric coating. Theoral medicament comprises between 0.1 g and 1 g of cetyl myristoleate.

[0022] Another embodiment of the invention provides an oral medicamentcomprising cetyl myristoleate and an enteric coating. The oralmedicament further comprises one or more of the components selected fromthe group consisting of glucosamine sulfate, chondroitin sulfate, seacucumber extract, hydrolyzed shark cartilage, collagen II, andmethylsulfonylmethane.

[0023] Even another embodiment of the invention provides a method oftreating a disease associated with the inflammation of tissues. An oralmedicament comprising cetyl myristoleate and an enteric coating isadministered to a human or animal. The disease to be treated is selectedfrom the group consisting of tendinitis, tenosynovitis, bursitis,chronic patellar tendinitis, Achilles tendinitis, fibrositis,inflammation of the spine, colitis, bronchitis, polymyalagia rheumatica,Crohn's disease, primary biliary cirrhosis, pericarditis, ulcerativecolitis, and Sjogren's syndrome.

[0024] Still another embodiment of the invention provides for a methodof treating a disease associated with an inflammatory condition thataffects joints. An oral medicament comprising cetyl myristoleate and anenteric coating is administered to a human or animal. The disease to betreated is selected from the group consisting of arthritis, chronicarthritis, Behcet's disease, ankylosing spondylitis, mixed connectivetissue disease, Reiter's syndrome, and synovitis.

[0025] Yet another embodiment of the invention provides for a method oftreating an autoimmune disease. An oral medicament comprising cetylmyristoleate and an enteric coating is administered to a human oranimal. The disease to be treated is selected from the group consistingof autoimmune Addison's disease, autoimmune hepatitis, Behcet's disease,lupus, antiphospholipid syndrome, multiple sclerosis, and essentialmixed cryoglobulinemia.

[0026] A further embodiment of the invention provides an oral medicamentcomprising microencapsulated cetyl myristoleate. The microencapsulationis resistant to dissolution in the stomach but predisposed todissolution in the intestine so as to prevent release of the cetylmyristoleate until the medicament is in the intestine.

[0027] Another embodiment of the invention provides for an oralmedicament comprising microencapsulated cetyl myristoleate. The oralmedicament comprises between 0.1 g and 1 g of cetyl myristoleate.

[0028] Even another embodiment of the invention provides for an oralmedicament comprising microencapsulated cetyl myristoleate The oralmedicament further comprises one or more of the components selected fromthe group consisting of glucosamine sulfate, chondroitin sulfate, seacucumber extract, hydrolyzed shark cartilage, collagen II, andmethylsulfonylmethane.

[0029] Still another embodiment of the invention provides for a methodof treating a disease associated with the inflammation of tissues. Anoral medicament comprising microencapsulated cetyl myristoleate isadministered to a human or animal. The disease to be treated is selectedfrom the group consisting of tendinitis, tenosynovitis, bursitis,chronic patellar tendinitis, Achilles tendinitis, fibrositis,inflammation of the spine, colitis, bronchitis, polymyalagia rheumatica,Crohn's disease, primary biliary cirrhosis, pericarditis, ulcerativecolitis, and Sjogren's syndrome.

[0030] Yet another embodiment of the invention provides for a method oftreating a disease associated with an inflammatory condition thataffects joints. An oral medicament comprising microencapsulated cetylmyristoleate is administered to a human or animal. The disease to betreated is selected from the group consisting of arthritis, chronicarthritis, Behcet's disease, ankylosing spondylitis, mixed connectivetissue disease, Reiter's syndrome, and synovitis.

[0031] A further embodiment of the invention provides for a method oftreating an autoimmune disease. An oral medicament comprisingmicroencapsulated cetyl myristoleate is administered to a human oranimal. The disease to be treated is selected from the group consistingof autoimmune Addison's disease, autoimmune hepatitis, Behcet's disease,lupus, antiphospholipid syndrome, multiple sclerosis, and essentialmixed cryoglobulinemia

[0032] Another embodiment of the invention provides for a suppositoryfor transrectal or transurethral delivery. The suppository comprisescetyl myristoleate in combination with a physiologically acceptablesolid carrier that is meltable at human or animal body temperature.

[0033] Even another embodiment of the invention provides for asuppository comprising between 1 mg and 3000 mg of cetyl myristoleate.

[0034] Still another embodiment of the invention provides for asuppository comprising cetyl myristoleate. The suppository furthercomprising one or more of the components selected from the groupconsisting of glucosamine sulfate, chondroitin sulfate, sea cucumberextract, hydrolyzed shark cartilage, collagen II, andmethylsulfonylmethane

[0035] Yet another embodiment of the invention provides a method fortreating a disease associated with the inflammation of tissues. Asuppository comprising cetyl myristoleate is administered to a human oranimal. The disease to be treated is selected from the group consistingof tendinitis, tenosynovitis, bursitis, chronic patellar tendinitis,Achilles tendinitis, fibrositis, inflammation of the spine, colitis,bronchitis, polymyalagia rheumatica, Crohn's disease, primary biliarycirrhosis, pericarditis, ulcerative colitis, and Sjogren's syndrome.

[0036] A further embodiment of the invention provides for a method oftreating a disease associated with an inflammatory condition thataffects joints. A suppository comprising cetyl myristoleate isadministered to a human or animal. The disease to be treated is selectedfrom the group consisting of arthritis, chronic arthritis, Behcet'sdisease, ankylosing spondylitis, mixed connective tissue disease,Reiter's syndrome, and synovitis.

[0037] Another embodiment of the invention provides for a method oftreating an autoimmune disease. A suppository comprising cetylmyristoleate is administered to a human or animal. The disease to betreated is selected from the group consisting of autoimmune Addison'sdisease, autoimmune hepatitis, Behcet's disease, lupus, antiphospholipidsyndrome, multiple sclerosis, and essential mixed cryoglobulinemia.

DESCRIPTION OF THE INVENTION

[0038] Cetyl myristoleate (CM) is a fatty acid ester of the followingstructure:

CH₃(CH₂)₁₅OCO(CH₂)₇ CH═CH(CH₂)₃CH₃

[0039] The invention provides novel methods of delivery of CM such thatgood absorption of the drug is achieved. These methods includetransdermal delivery devices, suppositories, enteric coatings, andmicroencapsulation.

[0040] The transdermal delivery devices of this invention are matrix ormonolithic-type laminated structures. Such transdermal delivery devicesare well known in the art. Cleary, Cosmetics and Toiletries, (1991)106:97-109. Transdermal delivery devices comprise a matrix layer of thedrugs, enhancer, or other components of the pharmaceutical compositionadmixed with a pressure sensitive adhesive and a backing layer. Thematrix serves as a reservoir for the drugs and as the means of affixingthe transdermal delivery devices to the skin. Alternatively, theadhesive can be provided in a layer separate from the matrix. Thetransdermal delivery devices preferably comprise a release liner layerthat is removed prior to use.

[0041] The virtually impermeable backing layer provides the top face ofthe transdermal delivery device and is the side furthermost away fromthe skin. The backing layer protects the transdermal delivery device andprevents the escape of the drug, adhesive, enhancer or other componentsof the pharmaceutical composition contained within the transdermaldelivery device.

[0042] The backing layer is preferably made of a material that is inertand incapable of absorbing the drug, adhesive, enhancer, or othercomponents of the pharmaceutical composition contained within thetransdermal delivery device. The backing layer may be comprised ofdermatologically acceptable films such as polyesters, polyurethanes,polyethylenes, polypropylenes, polyether amides, polyvinylchloride,polyvinylidene chloride, polyolefins, rubbers, synthetic resins, cloth,foils, and various laminates of these materials. This layer may bepigmented, metallized, or provided with a matte finish suitable forwriting. The backing layer may be occlusive (impermeable to gases andliquids) providing for skin hydration, or non-occlusive (allowingmoisture to pass through) providing for less skin hydration.

[0043] An adhesive layer is used to achieve contact between thetransdermal delivery device and skin. Preferably, the adhesive layerprovides instantaneous adhesion of the transdermal delivery device tothe skin while allowing for easy removal from the skin. The matrix layercan contain a pressure sensitive adhesive. Alternatively, an adhesivelayer can be independent of the matrix layer. Materials used in pressuresensitive adhesives include, but are not limited to natural rubber,styrene-butadiene-rubber polymers, styrene-butadiene-styrene orstyrene-isoprene block copolymers, polyisoprene, polyisobutylene, butylrubber, polyacrylates, silicone pressure-sensitive adhesives,polyisobutylene, and vinyl ether polymers.

[0044] The matrix layer contains the drug and may also contain adhesive,enhancer, or other components of the pharmaceutical composition. Themost simple transdermal delivery device design comprises theincorporation of the drug into a adhesive matrix covering the backinglayer. The drug may be dissolved or dispersed in the adhesive matrix, orbound to a non-soluble absorbent in the adhesive matrix. Alternatively,a porous pad soaked with an adhesive gel or liquid containing the drugcan be used.

[0045] The matrix may include other additives depending upon theparticular adhesive and drug used. For example, polyvinyl pyrrolidone(PVP) which inhibits drug crystallization, hygroscopic agents thatimprove the duration of wear, or additives that improve the physical(e.g. cold flow) or adhesive (e.g. tack cohesive strength) properties ofthe matrix can be added.

[0046] The matrix may also be non-adhesive. The non-adhesive matrixcomprises the drug, enhancer or other components of the pharmaceuticalcomposition dissolved or dispersed in a matrix or bound to a non-solubleabsorbent in the matrix. Suitable matrix materials include, but are notlimited to, polysaccharides such as starch, cellulose, hyaluronic acid,pectin, seaweed gums, polypeptides such as casein, albumin, keratin andcollagen, thermoplastics such as unvulcanized elastomers, nylon,polyethylene, polyurethane, acrylic resins, cellulose resins,polypropylene, polyethylene glycols, polyvinylacetates, polyvinylalcohols, and polyvinylpyrrolidones. In these peripheral adhesivesystems the non-adhesive matrix is lined with a separate adhesive layer.The peripheral adhesive system may also comprise a porous pad filledwith non-adhesive gel or liquid and equipped with peripheral adhesive.

[0047] Additionally, in contrast to homogeneous bulk concentrations ofthe drug in the matrix, a bulk concentration gradient of the drug may beestablished. Such gradients comprise drug adsorbents located in thedeeper layers of the matrix only. The gradients provide for uniformrelease rates.

[0048] The transdermal delivery device may include a release liner orpeel strip. The release liner covers the surface of the adhesive duringstorage and protects the adhesive and matrix, and maintains drugstability. The release liner may be made from any impermeable filmincluding, but not limited to, those materials specified for the backinglayer. Preferably, the release layer is comprised of silicone-coatedpolyester.

[0049] The transdermal delivery device may further be comprised ofpermeability enhancers to improve the permeability of the skin. Suchcompounds include, but are not limited to dimethylsulfoxide,dimethylformamide, decylmethylsulfoxide, 2-pyrrolidone,N-methyl-2-pyrrolidone, 1-dodecylazacylcloheptan-2-one, propyleneglycol, oleic acid, lactate ester of C₁₂C₁₈ aliphatic alcohol, lauryllactate, N,N-dimethylacetamide, polyethylene glycol monolaurate,glycerol monolaurate, lecithin, and sodium laurylsulfate. The amount ofpermeation enhancer included in the matrix will depend upon theparticular enhancer or enhancers used, the strength of the enhancer, thedesired increase in skin permeability, and the amount of drug to bedelivered. In most cases the enhancer will constitute in the range of 1to 20% by weight of the matrix.

[0050] The transdermal delivery devices of the invention may befabricated using procedures known in the transdermal delivery devicesart. In general, the matrix is formulated (i.e. the adhesive, drug(s),permeation enhancer, and any additives are mixed). The matrix is coatedon the backing or release liner layer, the solvent is removed from thematrix, and the backing or release layer is added.

[0051] The transdermal delivery devices can be fabricated usingconventional coating and laminating techniques and equipment which areknown to those skilled in the art. Transdermal delivery devices can befabricated by techniques including, but not limited to, solventevaporation film casting, melt extrusion, thin film lamination, and diecutting.

[0052] CM may also be delivered via a transrectal or transurethralsuppository. Typical carriers used in standardized suppositories aresolid and meltable at human or animal body temperature. Examples ofcarriers include, but are not limited to, beeswax or glycerol or both.

[0053] Other components that may be included in the transdermal deliverydevice and suppository CM drug formulations of the invention includecarriers such as water, azone, and propylene glycol, tackifers,pigments, dyes, and other additives that do not adversely affect themechanical or adhesive properties of the formulation.

[0054] The amount of CM incorporated in a transdermal delivery devicewill vary depending upon on the dosage required, the permeability of thepressure-sensitive adhesive materials, the thickness of thepressure-sensitive adhesive layer, and the length of time thetransdermal delivery device is to remain on the skin. The amount of CMincorporated in a suppository will vary depending upon the dosage of CMrequired.

[0055] The transdermal delivery device or suppository may containbetween 1 mg and 3000 mg of CM, preferably, the transdermal deliverydevice contains between 1 mg and 1000 mg of CM, more preferably thetransdermal delivery device contains between 200 mg and 600 mg of CM,more preferably the transdermal delivery device contains between 300 mgand 500 mg of CM. When CM is administered by transdermal delivery deviceor suppository, the effective therapeutic dose is normally in the rangeof 0.01 mg/kg/day to about 10 mg/kg/day, preferably, from 0.1 mg/kg/dayto about 5 mg/kg/day, preferably from 0.2 mg/kg/day to about 1.0mg/kg/day, and more preferably from 0.4 mg/kg/day to about 0.8mg/kg/day. These rates may vary depending upon the symptom or symptomsbeing treated.

[0056] The transdermal delivery device may be worn for a period of timeranging from between a few hours to 15 days, preferably the transdermaldelivery device is worn for 3 to 15 days, more preferably thetransdermal delivery device is worn for 5-10 days. The length oftreatment may vary depending upon the symptom or symptoms being treated.The transdermal delivery devices of the invention will preferably have abasal surface area of between 10 and 50 cm²; however, the surface areamay be smaller or larger.

[0057] Where suppositories are used to deliver CM the length oftreatment will range from 5 days to 30 days, more preferably, the lengthof treatment will range from 7 to 20 days, more preferably the length oftreatment will range from 10-15 days. The length of treatment may varydepending upon the symptom or symptoms being treated.

[0058] The transdermal delivery device or suppository may also containglucosamine sulfate, glucosamine hydrochloride, chondroitin sulfate, seacucumber extract, hydrolyzed shark cartilage, collagen II, andmethylsulfonylmethane. Preferably, the amounts of each of theseingredients range from between 1000 mg and 10 mg, preferably, theamounts of each of these ingredients range from between 750 mg and 50mg, even more preferably, the amounts of each of these ingredients rangefrom between 500 mg and 100 mg.

[0059] The transdermal delivery device or suppository may also containherbal ingredients. Preferably, the herbal ingredients are listed on theUSDA GRAS list. Examples of such herbal ingredients include, but are notlimited to, licorice root, cat's claw, black cohosh root, boswelliaherb, curcumin, ginger root, cinnamon bark, and bromelain. The amount ofeach of the herbal ingredients ranges from between 150 mg and 5 mg,preferably the amount of each of the herbal ingredients ranges frombetween 100 mg and 10 mg, even more preferably the amount of each of theherbal ingredients ranges from 75 mg to 20 mg.

[0060] The transdermal delivery device or suppository may also containvitamins or minerals, including, but not limited to, zinc, magnesium,and manganese.

[0061] Glucosamine sulfate, chondroitin sulfate, sea cucumber extract,hydrolyzed shark cartilage, collagen II, methylsulfonylmethane, herbalingredients, vitamins and minerals may also be administered orally alongwith the CM transdermal delivery device or CM suppositories.

[0062] Another aspect of the invention provides for the oraladministration of CM such that the drug is released when it reaches thesmall intestine. Release of CM into the small intestine is desirablebecause significantly better absorption of CM occurs in the smallintestine as compared to the stomach. CM may be delivered to the smallintestine using an enteric coating or microencapsulation.

[0063] Enteric coatings are used to deliver drugs to the small intestineand to protect drugs from inactivation by gastric enzymes or low pH.Targeted delivery is based upon the pH differences between these twoparts of the alimentary canal. Enteric coatings are selectivelyinsoluble substances that are insoluble in a low pH medium typicallyhaving a value less than about 5.5, but are soluble in a higher pHmedium typically having a value greater than about 5.5.

[0064] The coatings provide an impermeable barrier which will notreadily dissolve or disperse at the low pH of the gastric juices of thestomach. However, at the higher pH of the intestinal fluids the entericcoating will dissolve or disperse allowing for absorption of the drug.

[0065] CM is provided in an enterically coated, delayed releaseformulation. To prepare the delayed release enterically coatedformulations of CM, pharmaceutical preparations of CM are either formedinto a tablet or put into a capsule, and the tablet or capsule is coatedwith an enteric-coating material which dissolves at a pH ofapproximately 5.5 or greater. Suitable materials for enteric coatingsinclude, but are not limited to methacrylic acid copolymers, celluloseacetate phthalate, cellulose acetate succinate, and styrol maleic acidco-polymers, polymethacrylic acid/acrylic acid copolymer, hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate, hydroxyethylethyl cellulose phthalate, hydroxypropyl methyl cellulose acetatesuccinate, cellulose acetate tetrahydrophtalate, acrylic resin,cellulose acetate, timellitate, and phthalate or polyphthalate esters offilm-forming polymers such as those listed above. The choice ofenteric-coating material is not of significance as long as release isdelayed until the formulation reaches the small intestine.

[0066] To apply an enteric coating onto a dosage form substrate anorganic solvent may be used as a vehicle for coating the polymers.Examples of organic solvents include acetone, methanol, ethanol,isopropyl alcohol, ethyl acetate, methylene chloride, or mixturesthereof. Aqueous coating systems such as acrylic enteric polymers inlatex form, aqueous dispersions of cellulosic enteric polymers andaqueous ammonium salt solutions of cellulosic enteric polymers may alsobe used. The coating may be applied by spray coating, fluid bed coating,chemical vapor deposition, rotating pan coating, coascervation tank orany other process known in the art.

[0067] The formulations of the present invention may also beencapsulated in other time-release delivery systems such as a liposomedelivery system, polysaccharides exhibiting a slow release mechanism,salistic or other polymer implants or microspheres. In these timerelease delivery systems, the active compound is suitably protected withdifferentially degradable coatings, e.g., by microencapsulation andmultiple coatings, and such means effect continual dosing ofcompositions contained therein.

[0068] CM can also be coated by microencapsulation to provide forrelease in the small intestine instead of the stomach.Microencapsulation advantageously provides for better absorption of CM,taste abatement, and GI tolerability. Coacervation can be used tomicroencapsulate a drug. In coacervation, a hydrophilic substance isadded to a solution of colloid. Ranade, Drug Delivery Systems 5A, (1991)J Clin Pharmacol 31:2-16. If a drug is sensitive to water it may stillbe microencapsulated by protecting the drug from the aqueous environmentby coating the drug with polymers such as ethylcellulose, celluloseacetate phthalate, or carnauba wax prior to microencapsulation. CM mayalso be microencapsulated by spray coating, fluid bed coating, chemicalvapor deposition, rotating pan coating, or any other process know in theart.

[0069] Hydrophilic or hydrophobic substances or mixtures thereof may beused in microencapsulation. Natural polymers such as starch and otherpolysaccharides can be employed as well as synthetic polymers andphospholipids. Other materials suitable for use in microencapsulationinclude, but are not limited to, methacrylic acid ester copolymers,polysaccharides and their derivatives of natural or synthetic origin,cellulose derivatives including, but not limited to chitin derivatives,polymers of α and/or β-hydroxycarboxylic acids, polymers of glycolicacid, polymers of lactic acid, polymers of α-hydroxybutyric acid,polymers of α-hydroxyvaleric acid and/or their copolymers, or mixturesof such polymers and/or copolymers. Further, enteric coatings may beused in microencapsulation.

[0070] The thickness of the microencapsulation coat can be adjusted fromless than 1 μm to 200 μm by changing the amount of coating material. Themicroencapsulated drug may also be admixed or concentrically coated withother fractions of free or time-released drug. The admixtures may beplaced in either capsules or tablets and with other ingredients such asbinders, fillers, and lubricants.

[0071] When CM is administered with an enteric coating or bymicroencapsulation, the effective dose is normally in the range of 0.1g/kg/day to about 1 g/kg/day, preferably from 0.1 g/kg/day to about 0.5g/kg/day, and more preferably from 0.15 g/kg/day to about 0.25 g/kg/day.The length of treatment will range from 5 days to 30 days, morepreferably, the length of treatment will range from 7 to 20 days, morepreferably the length of treatment will range from 10-15 days. Thedosage and length of treatment may vary depending upon the symptom orsymptoms being treated.

EXAMPLES Example 1

[0072] The transdermal delivery devices of the invention can be testedusing the epidermal layers of human cadaver skin. Skin flux (μg/cm²/hr)may be determined from the steady-state slope of the plot of thecumulative amount of CM permeated through the skin versus time.

[0073] The transdermal delivery devices and suppositories of theinvention may further be tested by obtaining blood samples from healthyadult volunteers. A transdermal delivery device or suppositorycontaining CM may be administered to the volunteers. Blood is collectedat 1, 2, 4, 6, 8, 10, 14, 22 and 24 hours after application of the CMtransdermal delivery device or suppositories. The transdermal deliverydevice is then removed from the skin of the volunteers. The amount of CMin the blood is determined by thin layer chromatography (TLC). One weeklater, the same volunteers are given CM by mouth. Blood is collectedfrom the volunteers before the oral delivery and at 1, 2, 4, 6, 8, 10,14, 22, and 24 hours after delivery. The amount of CM in the blood isdetermined by TLC and is compared to the blood levels of CM delivered bythe transdermal delivery device.

Example 2

[0074] The microencapsulated and enterically coated CM compositions ofthe invention may be tested by obtaining blood samples from healthyadult volunteers. A dose of the microencapsulated or enterically coatedCM compositions are administered to the volunteers and blood iscollected at 1, 2, 4, 6, 8, 10, 14, 22 and 24 hours afteradministration. The amount of CM in the blood is determined by thinlayer chromatography (TLC). One week later, the same volunteers aregiven oral doses of the same CM compositions; however, these CMcompositions are not microencapsulated or enterically coated. Blood iscollected from the volunteers before the oral delivery and at 1, 2, 4,6, 8, 10, 14, 22, and 24 hours after delivery. The amount of CM in theblood is determined by TLC and is compared to the blood levels of CMdelivered by microencapsulated and enterically coated CM compositions.

1. A transdermal delivery device for the delivery of cetyl myristoleatewherein the transdermal delivery device contains between 1 mg and 3000mg of cetyl myristoleate.
 2. The transdermal delivery device of claim 1comprising: a backing layer; and a matrix layer underlying the backinglayer, the matrix layer comprising a mixture of cetyl myristoleate and apressure sensitive adhesive.
 3. The transdermal delivery device of claim1 wherein said matrix layer further comprises one or more of thecomponents selected from the group consisting of glucosamine sulfate,chondroitin sulfate, sea cucumber extract, hydrolyzed shark cartilage,collagen II, and methylsulfonylmethane.
 4. The transdermal deliverydevice of claim 1 wherein the device is worn for between 5 and 10 days.5. The transdermal delivery device wherein between 0.01 mg/kg/day and 10mg/kg/day of cetyl myristoleate is delivered.
 6. A method of treating adisease associated with the inflammation of tissues comprising affixingto the skin of an animal or human the transdermal delivery device ofclaim 1 wherein said disease is selected from the group consisting oftendinitis, tenosynovitis, bursitis, chronic patellar tendinitis,Achilles tendinitis, fibrositis, inflammation of the spine, colitis,bronchitis, polymyalagia rheumatica, Crohn's disease, primary biliarycirrhosis, pericarditis, ulcerative colitis, and Sjogren's syndrome. 7.A method of treating a disease associated with an inflammatory conditionthat affects joints comprising affixing to the skin of an animal orhuman the transdermal delivery device of claim 1 wherein said disease isselected from the group consisting of arthritis, chronic arthritis,Behcet's disease, ankylosing spondylitis, mixed connective tissuedisease, Reiter's syndrome, and synovitis.
 8. A method of treating anautoimmune disease comprising affixing to the skin of an animal or humanthe transdermal delivery device of claim 1 wherein said disease isselected from the group consisting of autoimmune Addison's disease,autoimmune hepatitis, Behcet's disease, lupus, antiphospholipidsyndrome, multiple sclerosis, and essential mixed cryoglobulinemia. 9.An oral medicament comprising cetyl myristoleate and an enteric coating,said coating being resistant to dissolution in the stomach butpredisposed to dissolution in the intestine so as to prevent release ofsaid cetyl myristoleate until said medicament is in the intestine. 10.The oral medicament of claim 9, wherein said enteric coating isresistant to dissolution in an environment having a pH less than about5.5.
 11. The oral medicament of claim 9 wherein said oral medicamentcomprises between 0.1 g and 1 g of cetyl myristoleate.
 12. The oralmedicament of claim 9, wherein said oral medicament further comprisesone or more of the components selected from the group consisting ofglucosamine sulfate, chondroitin sulfate, sea cucumber extract,hydrolyzed shark cartilage, collagen II, and methylsulfonylmethane. 13.A method of treating a disease associated with the inflammation oftissues comprising administering to a human or animal the oralmedicament of claim 9, wherein said disease is selected from the groupconsisting of tendinitis, tenosynovitis, bursitis, chronic patellartendinitis, Achilles tendinitis, fibrositis, inflammation of the spine,colitis, bronchitis, polymyalagia rheumatica, Crohn's disease, primarybiliary cirrhosis, pericarditis, ulcerative colitis, and Sjogren'ssyndrome.
 14. A method of treating a disease associated with aninflammatory condition that affects joints administering to a human oranimal the oral medicament of claim 9, wherein said disease is selectedfrom the group consisting of arthritis, chronic arthritis, Behcet'sdisease, ankylosing spondylitis, mixed connective tissue disease,Reiter's syndrome, and synovitis.
 15. A method of treating an autoimmunedisease comprising administering to a human or animal the oralmedicament of claim 9, wherein said disease is selected from the groupconsisting of autoimmune Addison's disease, autoimmune hepatitis,Behcet's disease, lupus, antiphospholipid syndrome, multiple sclerosis,and essential mixed cryoglobulinemia.
 16. An oral medicament comprisingmicroencapsulated cetyl myristoleate, said microencapsulation beingresistant to dissolution in the stomach but predisposed to dissolutionin the intestine so as to prevent release of said cetyl myristoleateuntil said medicament is in the intestine.
 17. The oral medicament ofclaim 16, wherein said oral medicament comprises between 0.1 g and 1 gof cetyl myristoleate.
 18. The oral medicament of claim 16, wherein saidoral medicament further comprises one or more of the components selectedfrom the group consisting of glucosamine sulfate, chondroitin sulfate,sea cucumber extract, hydrolyzed shark cartilage, collagen II, andmethylsulfonylmethane.
 19. A method of treating a disease associatedwith the inflammation of tissues comprising administering to a human oranimal the oral medicament of claim 16, wherein said disease is selectedfrom the group consisting of tendinitis, tenosynovitis, bursitis,chronic patellar tendinitis, Achilles tendinitis, fibrositis,inflammation of the spine, colitis, bronchitis, polymyalagia rheumatica,Crohn's disease, primary biliary cirrhosis, pericarditis, ulcerativecolitis, and Sjogren's syndrome.
 20. A method of treating a diseaseassociated with an inflammatory condition that affects jointsadministering to a human or animal the oral medicament of claim 16,wherein said disease is selected from the group consisting of arthritis,chronic arthritis, Behcet's disease, ankylosing spondylitis, mixedconnective tissue disease, Reiter's syndrome, and synovitis.
 21. Amethod of treating an autoimmune disease comprising administering to ahuman or animal the oral medicament of claim 16, wherein said disease isselected from the group consisting of autoimmune Addison's disease,autoimmune hepatitis, Behcet's disease, lupus, antiphospholipidsyndrome, multiple sclerosis, and essential mixed cryoglobulinemia
 22. Asuppository for transrectal or transurethral delivery comprising cetylmyristoleate in combination with a physiologically acceptable solidcarrier that is meltable at human or animal body temperature.
 23. Thesuppository of claim 22 wherein the suppository comprises between 1 mgand 3000 mg of cetyl myristoleate.
 24. The suppository of claim 22further comprising one or more of the components selected from the groupconsisting of glucosamine sulfate, chondroitin sulfate, sea cucumberextract, hydrolyzed shark cartilage, collagen II, andmethylsulfonylmethane
 25. A method of treating a disease associated withthe inflammation of tissues comprising administering to a human oranimal the suppository of claim 22, wherein said disease is selectedfrom the group consisting of tendinitis, tenosynovitis, bursitis,chronic patellar tendinitis, Achilles tendinitis, fibrositis,inflammation of the spine, colitis, bronchitis, polymyalagia rheumatica,Crohn's disease, primary biliary cirrhosis, pericarditis, ulcerativecolitis, and Sjogren's syndrome.
 26. A method of treating a diseaseassociated with an inflammatory condition that affects jointsadministering to a human or animal the suppository of claim 22, whereinsaid disease is selected from the group consisting of arthritis, chronicarthritis, Behcet's disease, ankylosing spondylitis, mixed connectivetissue disease, Reiter's syndrome, and synovitis.
 27. A method oftreating an autoimmune disease comprising administering to a human oranimal the suppository of claim 22, wherein said disease is selectedfrom the group consisting of autoimmune Addison's disease, autoimmunehepatitis, Behcet's disease, lupus, antiphospholipid syndrome, multiplesclerosis, and essential mixed cryoglobulinemia.